Synthesis of steroids by cyclization in nitro solvents

ABSTRACT

Synthesis of steroids by cyclization of a dienyne cyclization substrate to a steroid or A-nor steroid employing a primary or secondary aliphatic nitro compound as solvent, thereby forming an oxime ether group at the C-17 position of the resulting steroid (or at the corresponding position of the resulting A-nor steroid where that is the product of cyclization). This oxime group can be converted to an hydroxy group by reductive cleavage. Conversion of the cyclization products to steroids such as 17hydroxypregnan-20-ones and testosterone is facilitated. The method is also applied to cyclization of suitable substrates to bicyclic products.

United States Patent [191 Johnson et al.

[451 May 20, 1975 SYNTHESIS OF STEROIDS BY CYCLIZATION IN NITRO SOLVENTS[75] Inventors: William S. Johnson, Portola Valley; Douglas R. Morton,Palo Alto, both of Calif.; Michael B. Gravestock, Worthing, England [73]Assignee: The Board of Trustees of Leland Stanford Junior University,

Stanford, Calif.

[22] Filed: Apr. 26, 1973 [21] App]. No.: 354,532

[52] U.S. Cl. 260/3973; 260/397.4S; 260/397.47

[51] Int. Cl. C07C 169/22 [58] Field of Search Machine Searched SteroidsPrimary ExaminerElbert L. Roberts [57] ABSTRACT Synthesis of steroids bycyclization of a dienyne cyclization substrate to a steroid or A-norsteroid employing a primary or secondary aliphatic nitro compound assolvent,- thereby forming an oxime ether group at the C-17 position ofthe resulting steroid (or at the 5 Claims, No Drawings SYNTHESIS OFSTEROIDS BY CYCLIZATION IN NITRO SOLVENTS The invention described hereinwas made in the course of work under grants or awards from theDepartment of Health, Education and Welfare and the National ScienceFoundation.

This invention relates to the synthesis of steroids by a cyclizationprocess in which a cyclization substrate having an open chain structureincluding an acetylenic group at one end of the chain, two intermediatetrans olefinic groups and a cyclization initiator (which may be cyclicor acyclic) at the other end of the chain is caused to undergocyclization to form a tetracyclic product which, depending upon thecyclization initiator, is a steroid or an A-nor steroid. As will appearthe invention is also applicable to substrates which can be cyclized tobicyclic products.

It is known that the condensation of certain aldehydes with certainylides produces a substrate which is a dienyne and has the generalformula and steric configuration: I

Cyclization Initiator wherein some one or more of the carbon atoms ofthe dienyne group shown attached to Z may be substituted, for example bymethyl; the methyl group shown attached to the acetylenic group may beanother group such as ethyl or trimethyl silyl; and Z is a cyclizationinitiator such as one of those shown in Table 1 below. It is also knownthat this type of substrate can be cyclized in a suitable solvent in thepresence of a strong 20 J.A.C.S. 95, 4416 1973 See also Johnson,Gravestock, Parry, Myers, Bryson & Miles, J.A.C.S. 93, 4330 (1971 as tocyclization of certain substrates to bicyclic products.

TABLE I Steroid Resulting from Cyclization 3 a", (D I CH3 I II CH X CllCll cu X 3 x CH3 x Same as (2) above Cyclization Initiator CH3 no when aCH b CH when a H, b C H CH CH3 x 3 S S I TABLE 1 (Cont'd) SteroidResulting v i from Cyclization CH CH cu, I

as-cu; cu -s In Table I any of the methyl groups shown may be replacedby hydrogen or higher alkyl (e.g. ethyl or benzyl) and R may be methylor higher alkyl (e.g. ethyl), benzyl or protected hydroxymethyl. .X maybe hydroxyl, substituted hydroxyl such as methoxyl or ethoxyl, chlorine,bromine, also iodine (which, however,

is difficult to introduce) or F (which is difficult to remove). In theleft hand column of Table l the short solid line extending to the lowerright andterminating at a dashed line is the link to the remainder ofthe molecule. In the right hand column, the balance of the molecule (tothe right of the dashed line) is omitted in items (2) to (7); it is thesame as or very similar to that of the product of the cyclizationinitiator 1 In the thioketal group the linking group between the sulfuratoms may be (CH where n is an integer, e.g. 2-10; likewise in the ketalgroup.

Typical of these cyclization reactions are the followmg:

For the sake of simplicity, the conventional wedges (to indicate theB-configuration) and dotted line (to indicate the Ol-COllfigul'fltiOIl)at positions such as C-5, C-IO, etc. are omitted and it will beunderstood that the placement of H, CH etc. at these positions is as inthe natural steroids, the exception being that in those instances wherethe C-5 hydrogen or substituent is in the B-configuration it is soindicated. In general, the steric configurations at C17 is also shown,as in Flow Sheets Nos. 1,2 and 3.

It will be seen that the terminal group at the C-l7 positions of 4 and 6(and in the corresponding position in the A-nor steroid 2) is'a vinylgroup as in 2 and 6 or an acyl group as in 4. The presence of this groupintroduces difficulties in certain subsequent operations on the steroidproduct to convert it to a desired steroid' product such as al7-hydroxypregnan-20-one or testosterone. For example, if it is desiredto employ the steroid 4 as a precursor for testosterone thus or as aprecursor to a 1'7 hydroxypregnan-2O-one thus CH I 3 C:O '5 cu cu i- Iit is necessary to protect the A -olefinic group of4 from oxidation.Other difficulties are also encountered in the conversion of steroids 4and 6 as well as certain other cyclization products to the desired endproducts owing to the destructive effects of some of the requiredreagents on sensitive groups.

It is an object of the present invention to provide improvements in thesynthesis of steroids by the cyclization procedure described above andin the cited patent and scientific literature.

It is a particular object of the present invention to provide a methodwhereby the pendant group attached to the five-membered ring derivedfrom the acetylenic group of the substrate and resulting from itscyclization (which in the case ofa normal steroid is at the C-l7position) is more amenable to alteration to facilitate the synthesis ofcertain desired steroids such as 17-hydroxypregnan-ZO-ones andtestosterone.

The above and other objects will be apparent from the ensuingdescription and the appended claims.

We have discovered that, if the cyclization reaction typified byequations l (2), and (3) above is carried out in a solvent which is, orwhich includes as a substantial component, an aliphatic nitro compoundhaving at least one hydrogen attached to the carbon atom to which thenitro group is attached, an oxime ether is formed as follows:

In partial formula 9 R may be hydrogen; lower alkyl such as C to C alkyle.g. methyl or ethyl; aryl such as phenyl; halogen such as Cl or Br; ora protected hydroxy group such as methoxyl, higher alkoxyl, acyloxy suchas acetoxy or generally the group OCO.R wherein R may be C to C alkyl,phenyl, etc. or R may be a carbonate group OC0.0R wherein R is asdefined above. R and R are derived from the nitro aliphatic compound andare as defined below. In the partial formula 9 the remainder of themolecule (to the left of the five-membered ring) is omitted. The omittedportion may comprise a single ring fused with the fivemembered ring asin Example 1 below or it may comprise three fused rings as in thesteroids 2, 4, and 6 above.

We have further found that the oximes 9 lend themselves advantageouslyto conversion to other useful substances and (where they are tetracyclicsubstances,) to very useful products such as l7-hydroxypregnan- 20-onesand testosterone. Such conversions are considerably more facile than theconversion of similar cyclization products wherein the group attached tothe fivemembered D-ring at the C-17 position (or at the analogousposition in an A-nor steroid) is other than the acyl-oxime group shownin 9.

This method--the use as a solvent of an aliphatic nitro compound havingthe group a-No may be applied to any of the cyclization procedures andcyclization substrates described in the literature and patent referencescited above. Examples of cyclization initiators Z are set forth in TableI. Conditions of cyclization may be any of those which are described inthe aforesaid literature and patent references or as described below,with the proviso that the solvent be, or that it contain a substantialproportion of, an aliphatic nitro compound as described above. Theproportion of aliphatic nitro compound in the solvent is preferably 50%by weight or more, most advantageously by weight or more. Higherproportions of aliphatic nitro compound result in better yields.Co-solvents such as dichloromethane; 1,2-dichloroethane; otherchlorocarbons; l,l-difluoroethane; other fluorocarbons; and in generalany liquid which is inert to the cyclization reaction and in which thealiphatic nitro compound is soluble may be used.

The aliphatic nitro compound may be any of the primary or secondarynitro alkane series such as nitromethane, nitroethane, symmetrical andunsymmetrical nitro propanes; any of the various primary and secondary Cto C nitro alkanes, etc.; also cycloaliphatic nitro aliphatic compoundsprovided the carbon atom attached to the nitro group is a secondarycarbon atom having a hydrogen atom attached thereto such asnitrocyclohexane nitrocyclopentane, nitrocyclopropane, etc. The alkyl orcycloaliphatic group may be substituted by non-aliphatic groups and byhetero atoms and functional groups which do not interfere with formationof the oxime 9 and with the cyclization reaction. Examples ofnon-aliphatic substituents are phenyl (e.g. phenyl nitro methane),substituted phenyl (e.g. substituted by alkyl or halogen). The aliphaticgroups may have unsaturation. Mixtures of two or more aliphatic nitrocompounds may be used. Unsubstituted low molecular weight nitro alkanessuch as nitromethane, nitroethane and the nitropropanes are preferredbecause they are inexpensive, they are liquid at the reactiontemperatures and the excess is easily removed because the solvent isvolatile.

Examples 1, 2 and 3 below illustrate the method of the present inventionas applied to a bi-cyclic synthesis (Examples 1) a tetracyclic synthesisleading to an EXAMPLE 1 A solution of the tertiary alcohol 10 (seeJohnson et al., J.A.C.S. 93, 4330 (1971) I III contaminated with 12.5%of the isomeric homoallylic alcohol, was treated in dry nitroethane at78 with excess trifluoroacetic acid, followed by aqueous sodiumbicarbonate workup. This resulted in essentially complete conversion of10 with predominant formation of the epimeric oxime ethers l l in about80% yield of a 1:1 mixture of a-acetyl: B-acetyl isomers by vapor phasechromatography. A sample was purified by preparative tlc on silica gel1:9 EtOAc-hexane) to afford l1 (purity 97%, by vpc). The mass spectrumshowed a parent peak at m/e 305 (M+), and the infrared spectrum (liquidfilm) showed maxima at 1715 (C=O) and 1635 (C=N) cm. The nmr spectrum ofa chromatography fraction enriched in the a acetyl-epimer includedsinglets at 8 1.07 (3H) and 1.20 (6H) for the three methyl groupsattached to quaternary carbon atoms, and at 1.66 (3h) and 1.80 (3H) forthe isopropylidene methyl groups. In addition, there was a singlet at2.07 (3H, acetyl methyl), a doublet (J=6l-lz) at 1.90 (3H, N=CHCH and aquartet (J=6 Hz) at 6.83 (1H, N=CHCH Analytical samples of 1 1 aredifficult to obtain but degradation to a more readily purified productand analysis of the products of degradation established the structure1 1. Details will be found in a paper by Morton and Johnson, .l.A.C.S.Vol

95, p. 4419 (1973) entitled Acetylenic Bond Participation inBiogenetic-Like Olefinic Cyclizations. Cyclizations in Nitroalkanesolvents.

EXAMPLE 2 Cyclization of 1 in nitroethane followed by purification bypreparative tlc on silica gel (4:6 EtOAcpentane) and evuporativedistillation, yielded a 55:45 mixture of B-acetyl; a-acetyl oxime ethers12 in ca. 30% yield (purity 95%, by vpc); mass spectrum m/e 357 (M+).The infrared and nmr spectra were similar to those for l 1 and were incomplete accord with structure l2.

EXAMPLE 3 Treatment of a solution of 3 in dry 2-nitropropane withtrichloroacetic acid, followed by aqueous sodium bicarbonate workup andpurification by preparative tlc on silica gel (1:99 EtOAc-hexane:continuous elution for 4 hr) gave the isomeric oxime ethers 13 in 45%yield (ca. 1:1 mixture of 17-a-acetyl: 17,8-acetyl isomers by nmr).Evaporative distillation at 0.01 mm) afforded an analytically puresample (Anal. Found: C, 77.8; H, 10.0; N, 3.7); v 4 1712 (C=O), 1639(C=N) cm. The nmr spectrum (60 MHz, CCl TMS internal standard) includedsinglets at 5 0.58 (3H, C-18 of B-acetyl isomer), 0.93 (3H, C-l8 ofa-acetyl isomer), 0.99 (6H, CH9, both isomers) and at 1.86 (3H), 1.88(3H), 1.92 (3H), and 1.94 (3 H) for the methyl groups adjacent to thecarbonyl and oxime groups. In addition there were two singlets at 5.48and 5.52 (2H total) for the olefinic protons.

The oxime ethers 11 (Example 1), 12 (Example 2) and 13 (Example 3) aremixtures of isomers whose sep aration is very difficult. However incertain instances, as in the case of conversion of 13 to testosterone,the pendant groups at C-17 are replaced by a symmetrical group or atomwhich does not have the possibility of isomers, hence difficulty inseparation of the oxime ether isomers is of no importance; and even inthose cases (such as conversion of 13 to l7-hydroxypregnan- 20-one) theresulting isomer mixtures are useful or if a pure species such as17-a-hydroxypregnan-20-one is desired, separation or enrichment can beeffected by chromatography.

Flow Sheet 1 illustrates the manner in which the tetracyclic oxime etherof Example 3 may be converted to a mixture of isomeric17-hydroxypregnan-20-ones and Flow Sheet 2 illustrates how the sameoxime ether may be converted to testosterone. Example 4 gives detailsconcerning the steps of Flow Sheet No. 1 and Example 5 gives detailsconcerning the steps of Flow Sheet No. 2. Flow Sheet No. 3 illustrateshow the bicyclic oxime ether 1 1 can be converted to a ketone.

FLOW SHEET NO. 1

0-N=C(C\l OH all \4 STEP l all [Q H .5. H L:

STEP J. STEP 9' Mixture of l7-dand 17-,3 hydroxy 5 ,3 -pregnan-20 onesFLOW SHEET NO. 2

H OH O II FLOW SHEET NO 2 (Cont d) O COC I- NH coc gg-v TE I STEP 5 OCOCH Ago H aa ST P 6 STEP 7 OCOC H mu STEP 8 Testosterone Benzoate FLOWSHEET NO. 3

4 possible stereoisomers '1, till 6" EXAMPLE 4 Conversion of Oxime Ether13 to a Mixture of 17-04 and 17-3 hydroxypregnan-ZO-ones Step 1(reduction of the oxime ether 13 to the glycol 14) was carried out withexcess lithium aluminum hy dride in refluxing tetrahydrofuran in anatmsosphere of nitrogen, which cleaved the N-O bond and also reduced thecarbonyl group. 14 is a mixture of four stereoisomers which wereidentified (as a mixture) by nmr and infrared spectra. In Step 2 the Aolefinic bond of 14 was reduced by hydrogenation with palladium onactivated carbon in ethyl acetate at 23 to afford the diol 15 which wasoxidized in Step 3 by N- bromosuccinimide to afford 16 which is amixture of two stereoisomers of which l7-a-hydroxy-5B-pregnan- -one isone of the isomers.

EXAMPLE 5 Conversion of Oxime Ether 13 to dl-testosterone Benzoate InStep 1 (oxidative cleavage of the vicinal diol group), the diol 14 wastreated with periodic acid in methanol-water at 23 under nitrogen for 14hours to afford the ketone 17 which, in Step 2, was reduced by sodiumborohydride in ethanol at 23 under nitrogen to afford the alcohol 18which was converted in Step 3 to its benzoate 19 by means of benzoylchloride in pyridine at The C-3 position was oxidized in Step 4 toafford the ketone 20 by treatment with t-butyl chromate in acetic acid,and acetic anhydride and tetrachloroethylene under nitrogen at 85-95 forthree-fourths hours. The A -olefinic bond was reduced in Step 5 byhydrogen and palladium on activated carbon in ethyl acetate at 24 toafford the ketone 21 which was converted to the enol acetate 22 by'acetic anhydride in the presence of perchloric acid in ethyl acetate at23 for 10 minutes under nitrogen. The enol acetate 22 was treated withbromine in carbon tetrachloride and epichlorhydrin at 0 under nitrogento afford the bromoketone 23. The bromoketone 23 was treated withsemicarbazide hydrochloride which resulted in an intermediate (a,i-unsaturated semicarbazone not shown in Flow Sheet 2) which washydrolyzed with aqueous pyruvic acid to afford dl-testosterone benzoate24.

GENERAL DISCUSSION ill'lzk (1:0

a-nmck e l l l In this formula, the portion of the molecule to the lefttion of a substrate which may be a trans mono-or dienyne. This class ofoxime ethers lends itself to conversion, first by reductive cleavage toa glycol 27 HzR olli.

\L on or to a hydroxyketone group 29, thus (2 Hz K (1:0

These derivatives may then be converted by known steroid conversionreactions such as those illustrated in Flow Sheets Nos. 1 and 2 to moreuseful products such as testosterone, l7-hydroxypregnan-20-ones, etc, Asdescribed in Johnson, Markezich and McCarry, US. Patent application Ser.No. 281,380, the ylides which are condensed with aldehydes may beproduced in optically active form by resolution ofan acid which in turnis derived from an ester intermediate in the synthesis of the ylide. Ifan optically active ylide, e.g., the d form, is provided in such mannerand is condensed with an aldehyde, the cyclization substrate I will beoptically active and the resulting steroid will also be opticallyactive' rather than a racemic mixture.

The conversion of the glycol 27 and the hydroxy ke tones 29 to desiredend products may be carried out by standard conversion techniques whichare well known in steroid chemistry and which are exemplified in FlowSheets 1 and 2 and Examples 4 and 5.

Typical of such conversion techniques are reduction of an olefinic groupsuch as the A-olefinic group of 14 by catalytic hydrogenation; oxidationof a C-20 hydroxy] group to a keto group by N-broms succinimid'e;cleavage of the stereoisomeric diol mixture (as in 14) to a producthaving a C-l7 keto group (as in 17); protection of a sensitive alcoholgroup by forming the ester as in the case of 18-) 19 (Step 3 of FlowSheet No. 2). In some cases an ester is more easily crystallizedQFurtherexamples are oxidation of the C-3 position to a keto group withtert.-butyl-chromate (as in Step 4 of Flow Sheet No. 2); reduction of aA -olefinic group as in the conversion of 20 to 21 in Step 5 of FlowSheet 2 by catalytic hydrogenation; and the introduction of a N-olefinicgroup intothe A-ring of a steroid while protecting the C-3 keto group asin Steps 6, 7, and 8 of Flow Sheet 2 by bromination-dehydrobromination.I

As stated above one or more of the hydrogen atoms in the dienyne segmentof the molecule of] may be substituted, eg by methyl or ethyl. Anexample is the method described in Johnson and Gravestock US. Pat.application, Ser. No. 375,617, filed July 2, 1974 wherein the aldehydewhich is condensed with the ylide to produce the cyclization substrate Iis homologue typically prepared as follows:

I \l\ I) CH CH C(OCH '3 n 1 Eli lll 3o k) th The aldehyde 33 may becondensed with any of the ylides described in the patent and literaturereferences referred to in the second paragraph of this specification toproduce cyclization substrate 34 which, on cyclization in a solvent ofthe type described herein, produces a steroid (or an A-nor steroid) Weclaim: 1. In the method of cyclizing a substrate having in its moleculethe skeletal structure A to produce a cyclizatiin product having in itsmolecule the skeletal structure B wherein R selected from the classconsisting of hydrogen, lower alkyl, aryl, halogen and protectedhydroxyl; R is H or lower alkyl and X is a group derived from RCH C=-'the improvement which comprises conducting the cyclization in a solventwhich contains at least a major proportion of a primary or secondaryaliphatic nitro compound or mixture thereof, thereby forming acyclization product having in its molecule the skeletal structure Cwherein R and R are monovalent groups or a single bivalent group derivedfrom the nitro compound or mixture of nitro compounds.

wherein the carbon atoms shown may be variously substituted by alkylgroups and R is selected from the class consisting of hydrogen, loweralkyl, aryl, halogen and protected hydroxyl; and Z is a cyclizationinitiator, to a tetracyclic product having the skeletal structure IIwherein R is derived from Z and together with the carbon atoms to whichit is attached forms 5- or 6- membered carbocyclic A-ring and X is agroup derived from RCH C E the improvement which comprises conductingthe cyclization reaction in a solvent which contains at least a majorproportion of a primary or secondary aliphatic nitro compound, therebyforming a' cyclization product II in which the D-ring has the skeletalstructurelll wherein R and R are two monovalent groups or a singlebivalent group derived from the aforesaid aliphatic nitro compound.

3. The method of claim 2 wherein IA is selected so that II is a steroid4. The method of claim 2 followed by the step of reductive cleavage ofacyl-oxime ether group of II to a glycol group IV CF12 l'l 5. The methodof claim 1 wherein the aliphatic nitro compound is a low molecularweight nitro alkane having a primary or secondary carbon atom bonded tothe

1. IN THE METHOD OF CYCLIZING A SUBSTRATE HAVING IN ITS MOLECULE THESKELETAL STRUCTURE A
 2. In the method of cyclizing a compound IA
 3. Themethod of claim 2 wherein IA is selected so that II is a steroid
 4. Themethod of claim 2 followed by the step of reductive cleavage ofacyl-oxime ether group of II to a glycol group IV
 5. The method of claim1 wherein the aliphatic nitro compound is a low molecular weight nitroalkane having a primary or secondary carbon atom bonded to the nitrogroup.